Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC
SCLC 中铂诱导的脂质重编程和肿瘤免疫微环境
基本信息
- 批准号:10657660
- 负责人:
- 金额:$ 35.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAllograftingAntigen PresentationAntigen-Presenting CellsAttenuatedBiological AssayCell physiologyChronicClinicalCombination immunotherapyCombined Modality TherapyComplexDendritic CellsDevelopmentEnzymesExhibitsFatty AcidsFunctional disorderGeneticGenetically Engineered MouseGlutamineGoalsImmuneImmune EvasionImmune System DiseasesImmune checkpoint inhibitorImmune responseImmunosuppressionImmunotherapeutic agentImmunotherapyImpairmentInfiltrationLipidsMalignant NeoplasmsMalignant neoplasm of lungMediatingMediatorMetabolicMetabolismMitochondriaModelingMolecularMutationNaturePD-1/PD-L1PD-L1 blockadePeroxisome Proliferator-Activated ReceptorsPhenotypePilot ProjectsPlatinumPlayProteomicsRegulationRespirationRoleShapesSignal TransductionSurvival RateT cell infiltrationTP53 geneTechnologyTestingTherapeuticTumor AntigensTumor ImmunityTumor-DerivedValidationWorkantagonistanti-PD-1anti-PD-L1anti-PD-L1 antibodiesanti-tumor immune responsearginasecancer immunotherapycheckpoint therapychemotherapyefficacy evaluationexosomefatty acid metabolismhumanized mouseimmune checkpoint blockersimmune functionimmunogenicityimmunoregulationimprovedin vivo Modelinhibitorlipid metabolismlipidomicslong chain fatty acidmetabolomicsneoplasm immunotherapypatient subsetspharmacologicpre-clinicalprogramsresponsesmall cell lung carcinomatherapeutic targettranscriptome sequencingtumortumor microenvironmenttumor-immune system interactionsuptake
项目摘要
PROJECT SUMMARY
Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer with a five-year survival rate of less
than 5%. Immune checkpoint inhibitor (ICI) therapy such as anti-PD1/PD-L1 antibodies has demonstrated
unprecedented clinical activity in several difficult-to-treat cancers, with durable responses in a subset of patients.
Anti-PD-L1 antibodies such as atezolizumab, for example, have been recently received FDA approval as first
line treatment in combination with platinum-based chemotherapy for SCLC; however, the efficacy seems modest.
The mechanistic basis for the modest efficacy of immune checkpoint inhibitor in SCLC remains unknown but
mounting evidence suggests that the immunosuppressive nature of tumor microenvironment dictates the poor
efficacy of immunotherapy in SCLC. In addition, the potential impact of platinum-based chemotherapy on anti-
tumor immune response may also play an important role in determining the efficacy of immunotherapy.
Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses.
Emerging evidence indicates that the tumor microenvironment induces immune dysfunctional tumor-infiltrating
DC (TIDC), characterized with both increased intracellular lipid content and mitochondrial respiration. The
underlying mechanism, however, remains largely unclear. Here, we found that fatty acids-carrying tumor derived
exosomes (TDEs) induce immune dysfunctional DC to promote immune evasion. We also discover that platinum,
the front-line treatment for SCLC, further exacerbates TDE-induced DC dysfunction through reprograming of
glutamine-lipid metabolism in SCLC. Mechanistically, platinum rewires glutamine metabolism to promote fatty
acid synthesis, leading to enrichment of long chain fatty acids in TDEs. As a result, TIDCs uptake TDEs with
large amount of fatty acids that activates peroxisome proliferator activated receptor (PPAR) signaling, leading
to aberrant lipid accumulation and elevated FAO activity, which culminates in the induction of
immunosuppressive enzyme arginase 1 (Arg1) and consequently dysfunction in TIDCs. Genetic depletion or
pharmacologic inhibition of PPAR effectively attenuates TDE-induced DC-based immune dysfunction and
enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in
DCs and reveals that PPARlies at the center of metabolic-immune regulation of DCs, suggesting a potential
immunotherapeutic target. As such, targeting PPAR can be exploited to improve anti-cancer immunotherapy.
We will test our hypothesis through the following aims: Aim 1: To explore how TDEs activate PPAR and induce
Arg1 to drive DC dysfunction. Aim 2: To investigate how platinum rewires glutamine metabolism in SCLC to
induce dendritic cell dysfunction and immune evasion. Aim 3: To evaluate the efficacy of Chemo/anti-PD-
L1/PPAR inhibitor combination in SCLC.
项目总结
项目成果
期刊论文数量(0)
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Lingtao Jin其他文献
Lingtao Jin的其他文献
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{{ truncateString('Lingtao Jin', 18)}}的其他基金
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铂调节的脂质代谢在 tau 相关痴呆中的作用
- 批准号:
10713249 - 财政年份:2022
- 资助金额:
$ 35.45万 - 项目类别:
The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC
NFIB-MAST1信号在介导SCLC适应性顺铂耐药中的作用
- 批准号:
10553970 - 财政年份:2022
- 资助金额:
$ 35.45万 - 项目类别:
Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC
SCLC 中铂诱导的脂质重编程和肿瘤免疫微环境
- 批准号:
10419937 - 财政年份:2022
- 资助金额:
$ 35.45万 - 项目类别:
The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC
NFIB-MAST1信号在介导SCLC适应性顺铂耐药中的作用
- 批准号:
10599274 - 财政年份:2022
- 资助金额:
$ 35.45万 - 项目类别:
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- 批准号:
10285549 - 财政年份:2020
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